The present invention relates to an agent for the prophylaxis and treatment of glaucoma. More specifically, the present invention relates to an agent for the prophylaxis and treatment of glaucoma, which comprises a compound having a Rho kinase inhibitory activity as an active ingredient.
Glaucoma is caused by an abnormally high internal pressure of the eyeball, wherein the abnormally high pressure makes the eye grow dim or hurts the eye, which in turn fails the eyesight little by little possibly into blindness. Normally, an aqueous humor continuously circulates in the eyeball and maintains a constant intraocular pressure (10-20 mmHg). The pressure is maintained by the circulation of the blood and lymphocytes, elasticity of the eyeball wall, the performance of the control nerves and the like. An abnormality in any of them results in a rise of the intraocular pressure, which may develop glaucoma.
With the aim of preventing the intraocular pressure from rising or lowering an intraocular pressure that went up, for the prophylaxis and treatment of glaucoma, various drugs have been used. Known eye drops for the therapy of glaucoma include sympathetic agonists such as epinephrine, dipivefrine and the like. Due to mydriatic action, however, these eye drops enhance angle closure when administered to treat narrow angle glaucoma, and may cause not only an acute rise of the intraocular pressure, but also hypertension and pigmentation deposit. In addition, the parasympathetic agonists such as pilocarpine and the like cause side effects such as dark visual field due to miosis and congested eye, iris cyst, posterior synechia, cataract, retinal detachment and the like after a long-term use. Moreover, xcex2-adrenalin blockers such as timolol, pindolol and the like have been widely used, because they lower intraocular pressure by inhibiting the production of aqueous humor without acting on pupils. However, their use is limited, because xcex2-adrenalin blockers have been reported to cause side effects such as local dry feeling of the eye, allergic blepharitis, superficial keratitis and the like, as well as systemic side effects such as bradycardia, heart failure, asthmatic fit and the like. These side effects prevent application of the blockers to patients suffering from such symptoms. A recent suggestion of an aqueous humor outflow promoting effect of xcex1b 1-adrenalin blockers also suggests potential use of bunazosin hydrochloride and the like as a new therapeutic agent of glaucoma (Ikuo Azusa, Folia Ophthalmol. Jpn.,42,710-714,1991). However, the xcex11-adrenalin blockers are inevitably associated with conjunctival injection and miosis due to their vasodilating action.
In the meantime, a compound having a Rho kinase inhibitory activity has been reported to show a hypotensive effect on various hypertension model animals (Masayoshi Uehata, et al., Nature 389, 990-994, 1997). The Rho kinase has been confirmed to be present in corneal epithelial cells (Nirmala SundarRaj. et al., IOVS, 39(7) 1266-1272, 1998). However, it is unknown if Rho kinase is present in other ophthalmic tissues.
The pharmaceutical use of the compound having a Rho kinase inhibitory activity is disclosed in WO98/06433, and, as a use in the ophthalmic area, is taught to be useful for retinopathy. However, WO98/06433 does not disclose its usefulness against glaucoma or description suggestive of the effect.
As a compound having a Rho kinase inhibitory activity, a compound of formula (I) to be mentioned later has been reported (WO98/06433). The compound of formula (I) has been already known to be useful as an agent for the prophylaxis and treatment of disorders of circulatory organs such as coronary, cerebral, renal, peripheral artery and the like (e.g., a therapeutic agent of hypertension, a therapeutic agent of angina pectoris, a therapeutic agent of renal and peripheral circulation disorder, a suppressive agent of cerebrovascular contraction and the like), which is potent and long lasting, and also as a therapeutic agent of asthma (JP-A-62-89679, JP-A-3-218356, JP-A-4-273821, JP-A-5-194401, JP-A-6-41080 and WO95/28387).
However, these compounds of the formula (I) are not disclosed to be useful for glaucoma, and there is no description suggestive of such usefulness.
The present invention aims at solving the above-mentioned problems and provides a novel agent for the prophylaxis and treatment of glaucoma, which is superior in a prophylactic and therapeutic effect on glaucoma.
The present inventors have conducted intensive studies and found that a compound having a Rho kinase inhibitory activity also has an intraocular pressure lowering action, an optic disc blood flow improving action and an aqueous outflow promoting action, and that it is useful for the prophylaxis and treatment of various types of glaucoma, which resulted in the completion of the present invention.
Accordingly, the present invention provides the following.
(1) An agent for the prophylaxis and treatment of glaucoma, which comprises a compound having a Rho kinase inhibitory activity.
(2) The agent for the prophylaxis and treatment of glaucoma of (1) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the following formula (I) 
wherein
Ra is a group of the formula 
in the formulas (a) and (b),
R is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituent on the ring, or a group of the formula 
wherein
R6 is hydrogen, alkyl or formula xe2x80x94NR8R9 wherein R8 and R9 are the same or different and each is hydrogen, alkyl, aralkyl or phenyl, R7 is hydrogen, alkyl, aralkyl, phenyl, nitro or cyano, or R6 and R7 in combination show a group forming a heterocycle optionally having, in the ring, oxygen atom, sulfur atom or optionally substituted nitrogen atom,
R1 is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituent on the ring, or R and R1 in combination form, together with the adjacent nitrogen atom, a group forming a heterocycle optionally having, in the ring, oxygen atom, sulfur atom or optionally substituted nitrogen atom,
R2 is hydrogen or alkyl,
R3 and R4 are the same or different and each is hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyloxy, cyano, acyl, mercapto, alkylthio, aralkylthio, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl or azide, and
A is a group of the formula 
wherein
R10 and R11 are the same or different and each is hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl, or R10 and R11 show a group which forms cycloalkyl in combination and l, m and n are each 0 or an integer of 1-3,
in the formula (c),
L is hydrogen, alkyl, aminoalkyl, mono- or dialkylaminoalkyl, tetrahydrofurfuryl, carbamoylalkyl, phthalimidoalkyl, amidino or a group of the formula 
wherein
B is hydrogen, alkyl, alkoxy, aralkyl, aralkyloxy, aminoalkyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxycarbonylalkyl, xcex1-aminobenzyl, furyl, pyridyl, phenyl, phenylamino, styryl or imidazopyridyl,
Q1 is hydrogen, halogen, hydroxy, aralkyloxy or thienylmethyl,
W is alkylene,
Q2 is hydrogen, halogen, hydroxy or aralkyloxy,
X is alkylene,
Q3 is hydrogen, halogen, hydroxy, alkoxy, nitro, amino, 2,3-dihydrofuryl or 5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl;
and Y is a single bond, alkylene or alkenylene, and
in the formula (c),
a broken line is a single bond or a double bond, and
R5 is hydrogen, hydroxy, alkoxy, alkoxycarbonyloxy, alkanoyloxy or aralkyloxycarbonyloxy;
Rb is a hydrogen, an alkyl, an aralkyl, an aminoalkyl or a mono- or dialkylaminoalkyl; and
Rc is an optionally substituted heterocycle containing nitrogen,
an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(3) The agent for the prophylaxis and treatment of glaucoma of (1) or (2) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the following formula (Ixe2x80x2) 
wherein
Raxe2x80x2 is a group of the formula 
wherein
Rxe2x80x2 is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituent on the ring,
R1 is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituent on the ring, or Rxe2x80x2 and R1 in combination form, together with the adjacent nitrogen atom, a group forming a heterocycle optionally having, in the ring, oxygen atom, sulfur atom or optionally substituted nitrogen atom,
R2 is hydrogen or alkyl,
R3 and R4 are the same or different and each is hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyloxy, cyano, acyl, mercapto, alkylthio, aralkylthio, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl or azide, and is a group of the formula 
wherein
R10 and R11 are the same or different and each is hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl, or R10 and R11 show a group which forms cycloalkyl in combination and l, m and n are each 0 or an integer of 1-3,
Rb is a hydrogen, an alkyl, an aralkyl, an aminoalkyl or a mono- or dialkylaminoalkyl; and
Rc is an optionally substituted heterocycle containing nitrogen,
an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(4) The agent for the prophylaxis and treatment of glaucoma of (1) above, wherein the compound having a Rho kinase inhibitory activity is (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide, (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide and/or a pharmaceutically acceptable acid addition salt thereof.
(5) The agent for the prophylaxis and treatment of glaucoma of (1) above, which is administered to a local site in the eye.
(6) The agent for the prophylaxis and treatment of glaucoma of (5) above, which is in the form of an eye drop.
(7) A pharmaceutical composition for the prophylaxis and treatment of glaucoma, which comprises a compound having a Rho kinase inhibitory activity and a pharmaceutically acceptable carrier.
(8) The pharmaceutical composition for the prophylaxis and treatment of glaucoma of (7) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the following formula (I) 
wherein each symbol is as defined above, an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(9) The pharmaceutical composition for the prophylaxis and treatment of glaucoma of (7) or (8) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the following formula (Ixe2x80x2) 
wherein each symbol is as defined above, an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(10) The pharmaceutical composition for the prophylaxis and treatment of glaucoma of (7) above, wherein the compound having a Rho kinase inhibitory activity is (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide, (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide and/or a pharmaceutically acceptable acid addition salt thereof.
(11) The pharmaceutical composition for the prophylaxis and treatment of glaucoma of (7) above, which is for administration to local site in the eye.
(12) The pharmaceutical composition for the prophylaxis and treatment of glaucoma of (11) above, which is in the form of an eye drop.
(13) A method of the prophylaxis and treatment of glaucoma, which comprises administering an effective amount of a compound having a Rho kinase inhibitory activity to a patient.
(14) The method of the prophylaxis and treatment of glaucoma of (13) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the following formula (I) 
wherein each symbol is as defined above, an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(15) The method of the prophylaxis and treatment of glaucoma of (13) or (14) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the following formula (Ixe2x80x2) 
wherein each symbol is as defined above, an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(16) The method of the prophylaxis and treatment of glaucoma of (13) above, wherein the compound having a Rho kinase inhibitory activity is (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide, (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide and/or a pharmaceutically acceptable acid addition salt thereof.
(17) The method of the prophylaxis and treatment of glaucoma of (13) above, wherein the administration to a patient is that to a local site in the eye.
(18) The method of the prophylaxis and treatment of glaucoma of (17) above, wherein the administration to a patient is by instillation.
(19) Use of a compound having a Rho kinase inhibitory activity for the production of an agent for the prophylaxis and treatment of glaucoma.
(20) The use of (19) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the following formula (I) 
wherein each symbol is as defined above, an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(21) The use of (19) or (20) above, wherein the compound having a Rho kinase is an amide compound of the following formula (Ixe2x80x2) 
wherein each symbol is as defined above, an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(22) The use of (19) above, wherein the compound having a Rho kinase inhibitory activity is (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide, (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide and/or a pharmaceutically acceptable acid addition salt thereof.
(23) The use of (19) above, wherein the agent for the prophylaxis and treatment of glaucoma is for administration to a local site in the eye.
(24) The use of (23) above, wherein the agent for the prophylaxis and treatment of glaucoma is in the form of an eye drop.
(25) A commercial package comprising a pharmaceutical composition for the prophylaxis and treatment of glaucoma of any of (7) to (12) above, and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for the prophylaxis and treatment of glaucoma.